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University of Connecticut OpenCommons@UConn Doctoral Dissertations University of Connecticut Graduate School 6-1-2015 Development of New Synthetic Methods, Mechanistic Elucidation of Novel Organic Reactions Using Quantum Calculations, and Harnessing the Power of Continuous Flow Technologies Trevor A. Hamlin University of Connecticut - Storrs, [email protected] Follow this and additional works at: https://opencommons.uconn.edu/dissertations Recommended Citation Hamlin, Trevor A., "Development of New Synthetic Methods, Mechanistic Elucidation of Novel Organic Reactions Using Quantum Calculations, and Harnessing the Power of Continuous Flow Technologies" (2015). Doctoral Dissertations. 789. https://opencommons.uconn.edu/dissertations/789 Development of New Synthetic Methods, Mechanistic Elucidation of Novel Organic Reactions Using Quantum Calculations, and Harnessing the Power of Continuous Flow Technologies Trevor A. Hamlin, Ph.D. University of Connecticut, 2015 The development of synthetic methodologies can be aided and improved upon by a critical understanding of the mechanistic pathways at play during a chemical reaction. Computational modeling has proven very valuable in this endeavor. My graduate research has focused on three areas in particular: (1) development of synthetic methodologies, (2) quantum chemical modeling, and (3) utilization of emerging technologies. These topics are highly relevant in the literature today and serve as a foundation to aid researchers in generations to come. Development of New Synthetic Methods, Mechanistic Elucidation of Novel Organic Reactions Using Quantum Calculations, and Harnessing the Power of Continuous Flow Technologies Trevor A. Hamlin B. S. Albright College, 2010 A Dissertation Submitted in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy at the University of Connecticut 2015 i Copyright by Trevor A. Hamlin 2015 ii APPROVAL PAGE Doctor of Philosophy Dissertation Development of New Synthetic Methods, Mechanistic Elucidation of Novel Organic Reactions Using Quantum Calculations, and Harnessing the Power of Continuous Flow Technologies Presented by Trevor A. Hamlin B. S. Major Advisor ___________________________________________________ Nicholas E. Leadbeater, Ph.D. Associate Advisor ___________________________________________________ Robert R. Birge, Ph.D. Associate Advisor ___________________________________________________ José A. Gascón, Ph.D. Associate Advisor ___________________________________________________ Jing Zhao, Ph.D. Associate Advisor ___________________________________________________ Ronald J. Wikholm, Ph.D. University of Connecticut 2015 iii Acknowledgements Chemistry has been an intimate part of my life for many years now. Studying chemistry in Graduate School has been a challenging, yet extremely rewarding endeavor. At times, the process seemed too much to handle, but I was constantly reminded about the invaluable opportunity before me. My parents never had such an opportunity. They worked multiple jobs just so my sister and I could have a better life. My father is the hardest working person I know and serves as my inspiration for never giving up. I thank him for understanding my decision to move to Connecticut and then to The Netherlands and for always encouraging me to follow my own path. My mother passed away at the end of my fourth year of graduate school, a stressful time already, but managing it all allowed me to obtain a more mature worldview. She meant the world to me and it hurts to know that she will not be here to see me achieve all my goals. She serves as my source to always strive for nothing but the best. My wife has been my rock, serving to keep me grounded and always be a source of love and support. Mary Kate Hamlin and I were married at the beginning of my fourth year of graduate school and I am convinced it was her presence in my life that kept me going strong. I am grateful for her understanding nature while working around my graduate studies. She has supported me and all of my endeavors and I am confident we will happily grow old together. I would like to acknowledge my advisor Nicholas E. Leadbeater for always supporting my willingness to create. Dr. Leadbeater provided me the opportunity to build the theoretical chemistry component of the New Synthetic Methodology group from the ground up. He was one of the few who supported my desire for my Ph.D. to be comprised of both theoretical and experimental chemistry. I must also acknowledge my undergraduate advisor and mentor, Dr. Christian Hamann; for it was he who challenged me to go to pursue a Ph.D. in the first place. He pushed me to not only perform cutting edge computational research, but then also present the work across the United States at various local and national meetings. I value my friends and am confident that they allowed the process of obtaining a Ph.D. as enjoyable as possible. I would like to acknowledge Christopher Kelly, who has been a great motivator and source of chemistry knowledge. Christopher, along with Michael Mercadante, gave me the skills to allow me a proficient synthetic chemist. I thank them for their support and friendship. I would also like to acknowledge Jordan Greco, who is the kindest person I’ve ever met. He has been an amazing friend and has always extended himself for the service of others. Finally, I would like to thank my committee members for generously supporting me along the way towards my Ph.D. I would also like to acknowledge my former advisor Dr. Birge for giving me invaluable advice on my research and for also just being a good hearted person. Our time spent with each other, whether in the laboratory or out of the building, is always filled with great stories and endless laughter. Lastly I would like to thank Dr. Gascon for all the fruitful conversation we have had about calculations over that past few years. Your insight was extremely valuable and I thank you very much. iv Table of Contents List of Abbreviations vii List of Publications viii List of Contributions for Collaborative Projects ix List of Figures xii List of Tables xvi Chapter 1: Development of New Synthetic Methods 1 1.1 Introduction 1 1.2 Synthesis of Trifluoromethyl Containing Molecules 4 1.2.1 Background of TFMKs 4 1.2.2 Background on the Oxoammonium Salt 6 1.2.3 Synthesis of α-Trifluoromethyl Ketones Using an Oxoammonium Salt 10 1.2.4 Dehydrogenation of Perfluoroalkyl Ketones Using an Oxoammonium Salt 17 1.3 Synthesis of Perfluoroalkyl-Substituted Alkenes 24 1.3.1. Methylenation of Perfluoroalkyl Ketones using a Peterson Olefination 24 Approach 33 Chapter 2: Mechanistic Elucidation of Novel Organic Reactions Using Quantum Calculations 2.1 Introduction 33 2.2 Quantum Chemical Calculations of CF3 Cyclopropanes 35 2.2.1 Background on Accessing Trifluoromethylcyclopropanes via 1,3--Silyl 35 Elimination 2.2.2 Quantum Calculations on CF3 Cyclopropanes Formation via 1,3--Silyl 39 Elimination 2.3 Mechanistic Studies of Oxoammonium Salt Oxidation of Alcohols 51 2.3.1 Background on Developing Mechanistic Proposal for Oxoammonium Salt 51 Oxidation of Alcohols 2.3.2 Theoretical Studies of Oxidation of Methanol by an Oxoammonium Salt 62 2.4 Mechanistic Studies of Oxoammonium Salt Oxidation of Various Scaffolds 66 2.4.1 Background on Oxidation of Various Scaffolds by an Oxoammonium Salt 66 2.4.2 Oxidation to a C-O Bond - Alcohol Oxidation 67 2.4.3 Oxidation to a C-O Bond - Oxidative Functionalization of Isochromane 80 2.4.4 Oxidation to a C-N Bond - Oxidation of Imines 82 2.4.5 Oxidation of Activated C-H Bonds - Allylic Oxidation 84 2.4.6 Conclusions of Computational Studies 87 Chapter 3: Harnessing the Power of Continuous Flow Technologies 88 v 3.1 Background on Reaction Monitoring in Microwave and Continuous Flow 88 3.1.1 Raman Spectroscopy As a Tool For Monitoring Mesoscale Continuous-Flow 89 Organic Synthesis 3.2 Transition From Batch to Flow 103 3.2.1 A Continuous-Flow Approach to 3,3,3-Trifluoromethylpropenes: Bringing 103 Together Grignard Addition, Peterson Elimination, Inline Extraction, and Solvent Switching Closing Remarks 106 Appendix I: Preparation of Oxoammonium Salt 1.1a 113 Appendix II: Experimental Procedure for Developed Synthetic Methods 116 Appendix III: Quantum Chemical Calculation Details 147 Appendix IV: Experimental Procedures for Continuous Flow Processing 172 Appendix V: Permissions 184 vi List of Abbreviations Ar aryl atm atmosphere Bn benzyl BPR back-pressure regulator CDCl3 deuterated chloroform DBN 1,5-diazabicyclo(4.3.0)non-5-ene DBU 1,8-diazabicycloundec-7-ene DCM dichloromethane EDG electron-donating group Et2O diethyl ether EtOAc ethyl acetate Eq. molar equivalent EWG electron-withdrawing group GC gas chromatography HFIP hexafluoroisopropanol HRMS high resolution mass spectrometry LC liquid chromatography MeCN acetonitrile MS mass spectrometry NMR nuclear magnetic resonance OTf trifluoromethylsulfonate Ph phenyl ppm parts per million r.t. room temperature Temp temperature TBAF tetrabutylammonium fluoride tBu tert-butyl THF tetrahydrofuran TLC thin layer chromatography TMS, Me3Si trimethylsilyl TMS-CF3 trimethyl(trifluoromethyl)silane TFMK trifluoromethyl ketone vii List of Publications [10] Insight Theoretical and Experimental Studies of the Mechanism of Oxoammonium Salt Oxidations in Various Reaction Scaffolds using a Hydride Transfer Model. Hamlin, T. A.; Kelly, C. B.; Ovian, J. M.; Wiles, R. J.;Tilley, L. J.; Leadbeater, N. E. manuscript in preparation. [9] Real-time Monitoring of Reactions Performed Using Continuous-flow Processing: The Preparation of 3-Acetylcoumarin as an Example. Hamlin, T. A.; Leadbeater, N. E. In press. [8] Delocalization of Charge and Electron Density in the Humulyl Cation-Implications for Terpene Biosynthesis. Hamlin, T. A., Hamann, C. S., Tantillo, D. J. J. Org. Chem. 2015, 80, 4046. [7] A Continuous-Flow Approach to 3,3,3-Trifluoromethylpropenes: Bringing Together Grignard Addition, Peterson Elimination, Inline Extraction, and Solvent Switching. Hamlin, T. A.; Lazarus, G. M. L.; Kelly, C. B. Leadbeater, N. E. Org. Process. Res. Dev., 2014, 18, 1253. [6] 1,3-γ-Silyl-Elimination in Electron-Deficient Cationic Systems. Mercadante, M. A.; Kelly, C.
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